Approximately 20 million Americans develop peripheral neuropathy with annual costs to Medicare alone in excess of $3.5 billion. These diseases are poorly understood and therapeutic options are limited to non- existent. The hereditary forms of peripheral neuropathies present a unique window of opportunity to identify and dissect the key genes and pathways. In fact, these hereditary neuropathies, known as Charcot-Marie- Tooth disease (CMT), represent the most common inherited disorders in Neurology with 1/2500 individuals affected. Despite impressive success in gene identification in CMT, only ~30% of the genetic causes have been identified for the arguably most important, axonal subtype. Classic methods for gene identification, which depend on large pedigrees, become increasingly ineffective to resolve this problem. New high- throughput sequencing technology is now available that permits for the efficient analysis of whole genomes or highly informative proxies thereof, such as the exome, the entire collection of coding exons. Under the lead of Dr. Zuchner, Director of the Center for Human Molecular Genomics at the state-of-the-art Hussman Institute for Human Genomics, we have recently published the first exome sequencing study of a multigenerational pedigree and the first exome study on CMT and have now published several new genes identified with this method. We fully expect that this technology will add tremendously to resolving causative genes in relatively small CMT families not suitable for classic linkage analysis. The second PI of this proposal, Dr. Michael Shy, is Director of the largest CMT Clinic in the country as well as the PI of the NINDS/ORD funded Rare Disease Clinical Research Center (RDCRC) for genetic neuropathies and the MDA/CMTA funded North American Database and the North American CMT Network. Consequently, we have access to CMT patients throughout the world and propose in this grant a bold approach involving the application of high- throughput genomic technologies that will lead to the discovery of a considerable number of genes in a few years time. In addition we are pursuing genetic results with an innovative functional design in multiple biological systems, yeast, zebrafish, mammalian cell culture, that lend themselves to higher throughput studies. We have assembled an interdisciplinary team of clinicians, molecular and statistical geneticists, bioinformaticians, and molecular biologists to successfully apply these highly complex technologies. All data will be made available to publicly accessible databases laying the foundation for a future genomic repository for peripheral neuropathies. It is only by identifying the genetic causes of CMT that we will be able to study the function of encoded proteins and develop rational approaches to therapeutic intervention. Importantly, related axonal neuropathies, such as diabetic neuropathy, drug-induced neuropathies and degenerative diseases of motor and sensory neurons will greatly benefit from the results of such studies.